* Unknown * | ACSJCA | JCA11.2.5208/W Library-x64 | manuscript.3f (R5.1.i4:5009 | 2.1) 2021/10/27 08:51:00 | PROD-WS-116 | rq_8123997 |
6/23/2022 09:07:34 | 12 | JCA-DEFAULT
pubs.acs.org/JACS
Article
Biomolecule-Compatible Dehydrogenative Chan−Lam Coupling of
2 Free Sulfilimines
1
Tingting Meng,⊥ Lucille A. Wells,⊥ Tianxin Wang, Jinyu Wang, Shishuo Zhang, Jie Wang,
4 Marisa C. Kozlowski,* and Tiezheng Jia*
3
Cite This: https://doi.org/10.1021/jacs.2c04627
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sı Supporting Information
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ABSTRACT: Inspired by the discovery of a SN bond in the
collagen IV network and its essential role in stabilizing basement
membranes, sulfilimines have drawn much attention in the fields of
chemistry and biology. However, their further uptake is hindered
by the lack of mild, efficient, and environmentally benign protocols
by which sulfilimines can be constructed under biomoleculecompatible conditions. Here, we report a terminal oxidant-free
copper-catalyzed dehydrogenative Chan−Lam coupling of free
diaryl sulfilimines with arylboronic acids with excellent chemoselectivity and broad substrate compatibility. The mild reaction
conditions and biomolecule-compatible nature allow the employment of this protocol in the late-stage functionalization of complex
peptides, and more importantly, as an effective bioconjugation
method as showcased in a model protein. A combined experimental and computational mechanistic investigation reveals that an
inner-sphere electron-transfer process circumvents the sacrificial oxidant employed in traditional Chan−Lam coupling reactions. An
energetically viable concerted pathway was located wherein a copper hydride facilitates hydrogen-atom abstraction from the
isopropanol solvent to produce dihydrogen via a four-membered transition state.
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reactive methionine residues in whole proteomes.6 In addition,
the Tang group has developed a molecular probe, which can
image HOBr based on the formation of an intramolecular S
N bond in live cells and zebrafish.7
Considering the unique and intriguing properties of collagen
IV derived from sulfilimine cross-links, the derivatization of
peptides and proteins with this S(IV)-derived motif could
endow them with novel features. In this regard, N-Ar diaryl
sulfilimines, in sharp contrast to their S-alkyl counterparts,
represent a promising scaffold of great value since they are
more stable toward acid, base, water, or elevated temperature.1a However, their uptake in medicinal chemistry, as well
as chemical biology, was hampered by the lack of general and
biocompatible synthetic methods. Conventionally, N-Ar diaryl
sulfilimines could be prepared via oxidative imination of the
corresponding sulfides,1h,8 but the requisite strong oxidants
jeopardize their application in biomolecules. Friedel−Craftstype arylation of NH−sulfilimines with aryl fluorides, chlorides,
INTRODUCTION
Sulfilimines, the aza-analogues of sulfoxides, are a class of sulfur
(IV)-derived scaffolds, which possess a unique sulfur stereocentre if two carbon-based substituents on sulfur are not
identical. They have been exploited in organic chemistry as
building blocks, directing groups, and chiral axillaries, among
others.1 Moreover, chiral sulfilimines have also been developed
as ligands for transition-metal catalysts.2 In recent years,
sulfilimines have been added to the toolbox used by medicinal
chemists owing to their structural similarity to sulfoxides yet
possessing an additional site for derivatization.2,3
In 2009, Hudson and co-workers discovered a surprising
sulfilimine bond covalently cross-linking hydroxylysine-211
and methionine-93 to adjoin triple-helical protomers of
collagen IV, which is a highly conserved major component of
basement membranes across the animal kingdom.4 Moreover,
this unique bond plays a key role in the structural integrity of
basement membranes.5 The discovery of the first sulfilimine
bond in naturally occurring biomacromolecules has aroused
tremendous interest in this unusual structural motif in
biological contexts. For example, Chang, Toste, and coworkers have introduced an elegant biocompatible tagging
strategy to oxidize methionines to the corresponding
sulfilimines by treatment of oxaziridines, and successfully
achieved antibody−drug conjugates as well as identification of
© XXXX American Chemical Society
Received: April 29, 2022
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Figure 1. Conceptual design of the terminal oxidant-free process. (a) Preparative routes toward N-Ar diaryl sulfilimines and (b) design of Cu(I) to
Cu(II) transformation via an electron-transfer pathway.
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or nitrates successfully leads to the formation of arylated
products,9 but the substrate scope is limited to the electrondeficient arenes, thereby preventing its application in peptides
or proteins. In 2019, the Hashmi group disclosed an elegant
palladium-catalyzed arylation strategy of NH−sulfilimines with
aryl bromides or iodides.1h Unfortunately, the strongly basic
condition (KOtBu), as well as the high reaction temperature
(110 °C), renders this protocol unsuitable for the functionalization of peptides or proteins.
Therefore, a general, mild, and efficient synthetic route for
N-Ar diaryl sulfilimines that could be applied to peptides and
proteins is an unmet challenge.
With inexpensive and biofriendly catalysts, the absence of
acid, base, or elaborate ligands, mild and environmentally
benign reaction conditions, as well as the excellent functional
group compatibility, we hypothesized that copper-catalyzed
Chan−Lam coupling10 of free sulfilimines could be a powerful
tool to install diaryl sulfilimines on complex peptides or even
proteins. Indeed, the Bolm group developed Chan−Lam
couplings of sulfur(VI)-based sulfoximines11 and sulfondiimines12 using dry air as an external oxidant in alcoholic
solvents at ambient temperature. Ball and co-workers
introduced a seminal copper-catalyzed Chan−Lam coupling
of the pyroglutamate amide N−H bond at a naturally encoded
pyroglutamate−histidine dipeptide sequences.13 However, due
to the cross-nucleophile coupling nature, conventional Chan−
Lam couplings typically require the use of oxidants to facilitate
the oxidation of Cu(I) to Cu(II),14 which could be
problematic, especially in biological contexts, wherein proteins
and cells are sensitive to oxidative stress.15 In this regard, a
terminal oxidant-free Chan−Lam coupling process is an
appealing alternative (Figure 1a). A source of inspiration for
our design came from the classic electron-transfer-triggered
sulfoxide isomerization in metal complexes, in which an
electron could be transferred from a metal center to a
sulfur(IV) atom to form a sulfur-based radical anion (Figure
1b).16 Though this process, which also serves as a key step in
the transformation of cytochrome c from an electron-transfer
carrier to a peroxidase associated with the methionine 80
sulfoxide ligation, has been known for decades,17 it has not
been previously explored in small-molecule catalysis. We
envisioned that the electron-transfer process from a copper
catalyst to a sulfur(IV) atom of sulfilimines, which are
structurally similar to sulfoxides, could be leveraged to
circumvent the sacrificial oxidant required in traditional
Chan−Lam coupling reactions. As part of our investigations
in Chan−Lam coupling,18 herein, we report an unprecedented
copper-catalyzed dehydrogenative Chan−Lam coupling of free
diaryl sulfilimines with arylboronic acids, which does not
require a terminal oxidant. It permits facile access to a myriad
of N-Ar-diaryl sulfilimines and allows the synthesis of
sulfilimine-modified peptides and protein under biomoleculecompatible conditions.
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RESULTS AND DISCUSSION
Condition Optimization. In pursuit of a terminal oxidantfree coupling process, the model reaction between NHdiphenyl sulfilimine 1a and p-tolylboronic acid 2a was carried
out under an atmosphere of argon to preclude the influence of
air. While the model reaction proceeded in ethanol (0.3 M)
with Cu(OAc)2 (10 mol %), only an 11% assay yield of desired
product 3aa was obtained (entry 1, Table 1). Even so, an
analysis of the redox balance of this process is consistent with
two turnovers, which was supported by results with other
copper sources (entries 1−5). After a survey of copper catalyst
sources, CuBr was determined to be superior with a 71% yield
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model reaction led to the formation of 3aa in a slightly
diminished yield (81%) under an air atmosphere (entry 17),
which paves the road for the convenient operation of our
method on bioconjugation of proteins.
Substrate Scope. With the optimal conditions established,
the generality of arylboronic acid substrates was first
investigated (Table 2). The parent phenylboronic acid 2b
coupled with 1a to yield the corresponding sulfilimines 3ab
near quantitatively. Arylboronic acids possessing electronwithdrawing groups, such as 4-F (2c), 4-Cl (2d), 4-Br (2e), or
4-CF3 (2f), proved to be compatible coupling partners under
the optimal conditions, providing 3ac−af in 72−95% yields. A
meta-substituted arylboronic acid 2g was also well suited. The
neutral and oxidant-free conditions enabled a range of
functionalized arylboronic acids to be tolerated, including
those containing aldehyde (2h), ketone (2i), ester (2j), and
even the polymerizable vinyl group (2k) (54−97%). To our
delight, heteroarylboronic acids, such as 3-pyridyl (2l), 3quinolinyl (2m), and 6-quinolinyl (2n), proceeded smoothly
to furnish the corresponding products 3al−an in usable yields
(33−65%) by increasing the stoichiometry of 2a and extending
the reaction time. Moreover, a tyrosine-derived boronic acid
2o was also compatible with the transformation, providing 3ao
in an 87% yield. Remarkably, the coupling protocol displayed
excellent chemoselectivity favoring arylation of the NH−
sulfilimine 1a over arylation of the amide N−H bond.
We then turned our attention to the substrate scope of diaryl
sulfilimines using 4-tolylboronic acid (2a) as the coupling
partner. Electron-neutral 1a and 1b furnished 3aa and 3ba in
99 and 88% yields, respectively. NH−sulfilimines bearing
electron-withdrawing substituents, such as 4-F (1c), 4-Cl (1d),
4-CF3 (1e), and 2-Br (1f), performed very well, furnishing the
corresponding N-aryl sulfilimines (3ca-fa) in yields ranging
from 75 to 84% under slightly modified conditions. The
coupling chemistry proceeded smoothly with a 3,5-dimethyl
substituent appended to the sulfilimine, giving 3ga in an 84%
yield, albeit with an extended reaction time. Other functional
groups, such as 4-NHAc (1h) and 4-COOMe (1i), were also
viable, providing 3ha and 3ia in 80 and 64% yields,
respectively. This chemistry was also well accommodated by
heteroaryl NH−sulfilimines to generate 3ja−na in 64−77%
yields. Notably, the substrate scope of this chemistry could
even be expanded to S-aryl-S-alkyl sulfilimines, and 3op and
3pp were successfully obtained in 73 and 64% yields,
respectively.
Owing to the instability of the N-arylated sulfilimines
bearing an ortho-substituted aryl group on nitrogen, such as 1naphthyl or 2-tolyl, we successfully developed the sequential
coupling/oxidation cascade to directly afford the corresponding N-aryl sulfoximines 4aq and 4ar (Figure 2), which provides
a step-economic approach to prepare N-Ar-sulfoximines.
Inspired by the reactivity as well as the excellent chemoselectivity observed with tyrosine-derived substrate 3ao, the
suitability of the newly devised copper-catalyzed Chan−Lam
coupling for use in sulfilimine-modified peptides was
investigated (Table 3). The introduction of second amino
acid to the tyrosine-based boronic acid 2o was initially
investigated. As depicted in Table 3, Tyr containing amino
acids at N-terminal positions bearing diverse functionalities
was not detrimental, affording dipeptides 6aa−ae in good to
excellent yields. These results highlight the excellent chemoselectivity of our protocol, favoring C−N bond coupling of
sulfilimine N−H bonds over C−O, C−S, or C−N bond
Table 1. Optimization of the Copper-Catalyzed CrossCoupling Reaction of 1a and 2aa
b
entry
[Cu]/mol %
solvent
conc./M
assay yield /%
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4
5
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12c
13d
14c
15c
16c
17f
Cu(OAc)2/10
Cu(acac)2/10
CuCl2/10
CuCl/10
CuBr2/10
CuBr/10
CuBr/10
CuBr/10
CuBr/10
CuBr/10
CuBr/10
CuBr/10
CuBr/10
CuBr/5
CuBr/2.5
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
iPrOH
tBuOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
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0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
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81
CuBr/5
a
Unless otherwise stated, reactions were carried out with 1a (0.3
mmol), 2a (2.3 equiv), and a copper source (10 mol %) in a solvent at
room temperature under an argon atmosphere for 24 h. bAssay yields
were determined by 1H NMR spectroscopy of unpurified reaction
mixtures using 0.1 mmol (7.0 μL) CH2Br2 as the internal standard.
c
2a (1.5 equiv). d2a (1.2 equiv). eIsolated yield. fUnder an air
atmosphere.
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of 3aa obtained (compare entry 6 vs entries 1−5). Forging
ahead with CuBr as an optimal copper source, three other
commonly used alcoholic solvents (MeOH, iPrOH, and
tBuOH) were investigated (entries 7−9). When iPrOH was
employed as a solvent, 3aa was obtained in an 86% yield (entry
8). Other alcohols, unfortunately, produced 3aa in much lower
yields (entries 7, 9). Concentration was also discovered to be a
key factor. Interestingly, when the reaction concentration was
decreased from 0.3 to 0.1 M, the assay yield of 3aa could be
improved from 86% (entry 8) to 99% (entry 11).
Subsequently, the amount of 2a could be successfully
decreased to 1.5 equiv, and the assay yield of 3aa remained
the same (entry 12). However, the utilization of 1.2 equiv of 2a
resulted in a slightly diminished yield (85%, entry 13).
Gratifyingly, the copper loading could be successfully lowered
to 5 mol %, and 3aa could be generated in a 99% assay yield
and a 99% isolated yield (entry 14). Further reduction of the
copper source to 2.5 mol %, however, led to a lower yield (75%
yield 3aa, entry 15). A control experiment was also conducted
in the absence of any copper source, and no desired product
formed, which confirmed the essential role of the copper
species in the transformation (entry 16). Therefore, the
optimal condition for copper-catalyzed Chan−Lam coupling of
free sulfilimines was determined to be: free sulfilimine 1a as a
limiting reagent, boronic acid 2a (1.5 equiv) as a coupling
partner, CuBr (5 mol %) as a catalyst in iPrOH (0.1 M) under
an argon atmosphere at room temperature for 24 h.
Interestingly, despite no need for an external oxidant, the
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Table 2. Substrate Scope of Arylboronic Acids and Sulfilimines in Copper-Catalyzed Chan−Lam Couplingabcdef
a
Reaction conditions: 1 (0.3 mmol), 2 (1.5 equiv), and 5 mol % CuBr in iPrOH (3.0 mL) under an argon atmosphere at room temperature for 24
h. b36 h. c2 (2.0 equiv), 48 h. d48 h. e2 (2.0 equiv), 36 h. f2 (2.0 equiv), 72 h.
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tyroservatide (5k,l),20 were also well suited to the coupling,
providing 6aj−l in good yields. Of note, an angiotensin
converting enzyme (ACE) inhibitor tripeptide used to
decrease angiotensin I21 performed well under the optimal
conditions to produce 6am in a 68% yield. To evaluate the
robustness of our coupling protocol, even more complex
Tyr(B(OH)2)-containing oligopeptides beyond tripeptides
were explored. At the outset, a series of bioactive tripeptides
[glutathione, tripeptide-10,22 melanostatin,23 and two ACE
inhibitors (Gly−Pro−Met−NH2 and Gly−Pro−Leu−NH2)24]
were decorated with a Tyr(B(OH)2) residue at the N-terminus
to afford 5n−r. These substrates proved successful partners in
the coupling reactions with 1a to generate the corresponding
products 6an−r. The terminal oxidant-free Chan−Lam
formation of hydroxyl O−H bonds, thiol S−H bonds, amide
N−H bonds, or indole N−H bonds. It is worth noting that
methionine (Met, 5b) and cysteine (Cys, 5c), which were not
amendable in the previous sulfide imination strategy,6 could be
successfully employed in our coupling protocol. It is also
apparent that the position of the phenylboronic acid
containing a residue at either the N-terminus or the Cterminus (6af−ah) does not significantly affect the efficiency.
We next investigated the compatibility and superiority of this
Chan−Lam coupling to modify more complex peptides. The
Tyr(B(OH)2) derivative of oglufanide, a tripeptide immunomodulator in the treatment of hepatitis C (5i),19 coupled with
1a to furnish 6ai in an 85% yield. The aspartame derivate 5j, as
well as two anticancer tripeptides, tyroserleutide and
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temperature. As disclosed in Figure 3b,c, the sulfilimine bond
in protein 7 (50 μM) was relatively stable in PBS buffer (pH
7.4) or under oxidative conditions (5 mM sodium periodate
and 5 mM hydrogen peroxide), as evidenced by no statistically
significant variation in biotinylation levels after 12 h, as
quantified by western blotting. Nevertheless, the SN bond is
sensitive to acidic (pH 5.0, 0.2 mM NaH2PO4), basic (pH
10.0, 50 mM NMM), reductive (5.0 mM DTT), and
Dulbecco’s modified Eagle medium (DMEM, with 10% v/v
fetal bovine serum) conditions, with a considerable decrease of
biotinylated protein 7 (25−60% retained). Among all of the
factors examined, high temperature caused the most
degradation of the sulfilimine motif, leading to significant
cleavage of the sulfilimine bond in a very short period of time
(10 or 30 min), which is consistent with the previous
observations from Wells.27 In addition, significant degradation
of a sulfilimine-based covalent linker in protein 7 occurred
upon treatment with sodium selenite (5 mM), attesting to
selective reduction of the SN bond in protein under
physiological conditions based on Tang’s pioneering report.7b
Mechanistic Studies. To gain mechanistic insight into the
unprecedented terminal oxidant-free Chan−Lam cross-coupling reaction, several control experiments were performed.
The oxidant in the conventional Chan−Lam coupling is
believed to facilitate the oxidation of Cu(I) to Cu(II) or
Cu(III) in the catalytic cycle.10 Due to the terminal oxidantfree nature of the Chan−Lam coupling of free sulfilimines,28
along with our report on oxidant-free photoredox Chan−Lam
coupling of free sulfoximines,18a the impact of light on the
newly devised coupling reaction was initially explored. When
the model reaction between 1a and 2a was performed in the
dark under otherwise identical conditions, 3aa was still
obtained in a 94% yield (Figure 4a), suggesting that light is
not integral to this process. To discover the oxidation states of
the copper species, spectroscopic studies were conducted
under an argon atmosphere. Electron paramagnetic resonance
spectroscopy (EPR) (Figure 5a) of the reaction mixture
revealed a Cu(II) signal. When CuBr was only dissolved in
iPrOH or mixed with p-tolylboronic acid 2a, no noticeable
signal was observed via EPR, in agreement with the presence of
a Cu(I) species. Surprisingly, a Cu(II) peak appeared when
CuBr was mixed with free sulfilimine 1a together in iPrOH.
This unexpected result supports that 1a could facilitate the
oxidation of Cu(I) to Cu(II), replacing the role of an oxidant
in classical Chan−Lam coupling. To further verify this finding,
a series of UV−vis experiments were performed (Figure 5b).
There was no obvious UV absorption of a CuBr solution above
400 nm, whereas a CuBr2 solution exhibited a characteristic
band on 590 nm, which is consistent with the d−d transition of
Cu(II) species. In addition, the UV band shifted to 760 nm
after 1a was added to a CuBr2 solution, presumably due to the
coordination of 1a to Cu(II). As expected, a characteristic UV
absorption of Cu(II) species appeared at 690 nm when CuBr
was mixed with 1a, supporting the pivotal role of 1a in the
transformation of Cu(I) to Cu(II). Furthermore, the addition
of radical scavengers [2.0 equiv of tetramethylpiperidine Noxide (TEMPO) or 1,4-dinitrobenzene (p-DNB)] to the
model reactions only had a modest effect, affording 3aa in 89
and 74% yields, respectively (Figure 4b). This result implies
that free radicals are not major intermediates in the
transformation, although caged radical pairs are still plausible.
We hypothesized that the byproduct of the transformation
might be dihydrogen gas, which was confirmed by the
Figure 2. Sequential coupling/oxidation cascade to prepare N-aryl
sulfoximines directly from free sulfilimines and arylboronic acids.
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coupling was an effective tool to install diphenyl sulfilimine
moieties on two endogenous opioid receptor agonists
endomorphin-1 (6as) and met-enkephalin (6at) in 61 and
58% yields, respectively. Remarkably, the chemistry was well
accommodated even with deltorphin I (5u), an exogenous
opioid receptor agonist,25 providing the heptapeptide derivative 6au in a 63% yield under a slightly modified reaction
condition, highlighting the breadth and expediency of this
procedure.
Chan−Lam Coupling-Based Bioconjugation in Model
Protein Halotag 7. Encouraged by the broad tolerance to
different peptides, as depicted in Table 3, we then sought to
develop the copper-catalyzed Chan−Lam coupling of free
sulfilimines as a selective protein conjugation method based on
the C−N bond formation of free sulfilimines. A major chemical
challenge for such an unprecedented bioconjugation method
under pH-neutral physiological conditions is the relatively
weak nucleophilicity of free sulfilimines, which demands an
exceptional level of chemoselectivity relative to more
nucleophilic amino acids, such as cysteine, lysine, tyrosine, or
serine. Halotag 7, the 33 kDa monomeric protein, is a
genetically engineered derivative of a dehalogenase, which can
efficiently and specifically form a covalent bond with a
synthetic ligand.26 Therefore, it was selected as a model
protein substrate for this study. As illustrated in Figure 3a, we
initialized the investigation by installing a PEG linker tethered
with a phenylboronic acid motif on D106 of halotag 7 to
provide the viable protein substrate, namely halotag 7′, for the
subsequent coupling protocol (see details in Figures S4 and
S5). The boronic acid group serves as a point for further
functionalization of the protein via the copper-catalyzed
Chan−Lam coupling with free sulfilimine 1q. In practice, the
exposure of 330 μM halotag 7′ to the standard catalytical
condition resulted in the formation of cross-coupling product 7
with a 43% conversion based on intact protein mass analysis.
As discovered by the Hudson group, the sulfilimine covalent
cross-link in collagen IV appears as an adaptation of the
extracellular matrix in response to mechanical stress in
metazoan evolution, and thus serves as a key reinforcement
that stabilizes networks as well as basement membranes.5
Thus, the stability of sulfilimines in the context of proteins
under various physiologically relevant conditions stands as an
interesting problem. Nevertheless, our biomolecule-compatible
terminal oxidant-free Chan−Lam coupling offers an enabling
platform to tackle this issue. Purified protein 7 was incubated
under a variety of biologically relevant conditions at room
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Table 3. Scope of Peptides in Copper-Catalyzed Chan−Lam Coupling with 1aabcd
a
Reaction conditions: 1a (0.1 mmol), 5 (1.5 equiv), and 10 mol % CuBr in iPrOH (1.0 mL) under an argon atmosphere at room temperature for
24 h. b48 h. c1a (0.1 mmol), 5 (1.5 equiv), CuBr (10 mol %), MeOH (1.0 mL), and 48 h. d1a (0.05 mmol), 5 (1.5 equiv), CuBr (10 mol %),
MeOH (1.0 mL), H2O (1.0 mL), DMF (0.15 mL), and 48 h. Yields provided in square brackets are reported as a % conversion determined from
reverse-phase HPLC. Tyrs: 4-diphenylsulfiliminyl tyrosine.
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Figure 3. Cross-coupling reaction of Halotag 7′ with the biotin group containing NH−sulfilimine 1q. (a) Scheme for the reaction of halotag 7′
with the biotin containing NH−sulfilimine 1q. General reaction conditions: halotag 7′ (330 μmol) treated with 1q (10.0 equiv) using CuBr (1.0
equiv) in a MeOH/phosphate-buffered saline (PBS) solvent (v/v = 8/92, pH 7.4) for 56 h at room temperature. (b) Western blotting image of
stability experiments of purified protein 7 after incubating under the given conditions at room temperature for 12 h. (c) Quantification of the
western blotting results with image J software. The untreated purified protein 7 was used as a standard (chemiluminescence intensity = 1.0 in
Figure 3c). An average of two standard bands was used for each experiment.
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examination of the reaction headspace via gas chromatography
(GC) (see details in Table S2 and Figures S7−S10). To shed
light on the source of H2, mass spectroscopy was used to
monitor the gaseous byproduct formed while deuterated
methanol was employed as a solvent. A signal corresponding
to HD was observed, supporting that one hydrogen atom of H2
arises from the alcoholic solvent. When competitive external
ligands, such as 4,4-di-tert-butyl bipyridine (dtbpy) or 2,9dimethyl-1,10-phenanthroline (neocuproine), were added to
the reaction system containing CuBr, the reaction rates were
inhibited dramatically (Figure 4c). Together with UV−vis
studies (see above), this result supports coordination of
sulfilimine 1a to a copper catalyst playing a pivotal role in the
catalytic cycles. Overall, the data are consistent with an innersphere electron-transfer process, enabling the formal oxidation
of Cu(I) to Cu(II).
To understand the origin of the hydrogen evolution in this
reaction, a density functional theory (DFT) study was
initiated. Initial calculations were conducted using Gaussian
1629 with B3LYP/6-31G(d), Cu:SDD30 to explore different
pathways. Key steps were further evaluated with SMD-2propanol-BP86-d3/6-311G(d,p), Cu:SDD//BP86-d3/6311G(d,p), and Cu:SDD,31 a method previously used to
calculate pathways with copper hydrides.32
With the presence of copper (II) confirmed through EPR
and UV−vis, a Born−Haber cycle (Figure S13) was used to
calculate the redox potential of Cu+ and 1a to Cu2+ and the
anion radical of 1a.33 The favorable potential of 0.5 V vs SHE
indicates that NH−sulfilimines can oxidize Cu(I) to Cu(II),
providing a possible explanation for the presence of Cu(II) in
the reaction solution.
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The remaining pathways were investigated commencing
from the triplet Cu(II) species I, as illustrated in Figure 5c and
d. A radical pathway (Figure 5c) can form H• by dissociation
from the sulfilimine (II). The H• then abstracts the hydrogen
from iPrOH via transition state III with a barrier of 21.9 kcal/
mol. While transition state III is accessible at room
temperature, the formation of a radical is inconsistent with
the experimental results, showing that TEMPO does not
inhibit the reaction. Another pathway (Figure 5d) forms
hydrogen gas through a copper hydride species. The copper
hydride (V) arises from insertion into the N−H of the
sulfilimine via transition state IV. From V, a four-membered
transition VI allows the copper hydride to abstract H+ from
coordinated iPrOH to form hydrogen gas. The formation of
copper hydride and the further formation of hydrogen gas is
plausible at room temperature since the largest barrier in the
pathway is 21.1 kcal/mol (IV).
On the base of the combined experimental results and
computational studies, a plausible mechanism is outlined in
Figure 5e. Initially, CuBr binds to NH−sulfilimines 1 to give
Cu(I) species A, which undergoes an inner-sphere electrontransfer process to yield Cu(II) intermediate B featuring a
radical anion NH−sulfilimine ligand. Meanwhile, the solvent
iPrOH coordinates to the copper center to generate B.
Subsequently, the insertion of Cu(II) into the N−H bond of
the sulfilimine leads to the formation of three-membered
transition state C. Cu(II)-facilitated homolysis of the O−H
bond of iPrOH occurs to give a formal Cu(III) hydride species
D, which can release the hydrogen gas, as revealed by
headspace GC analysis, via a feasible four-membered transition
state. The resultant Cu(III) species F can undergo transmetallation with boronic acid 2 to produce arylated Cu(III)
species G, followed by reductive elimination and ligand
exchange with 1 to generate the product 3, and close the
overall catalytic cycle.
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CONCLUSIONS
In summary, a terminal oxidant-free copper-catalyzed dehydrogenative Chan−Lam cross-coupling of NH−sulfilimines
with arylboronic acids has been achieved. This method
obviates the need for stoichiometric oxidants of classic
Chan−Lam couplings, enables the facile syntheses of a variety
of N-arylated diaryl sulfilimines, and is also compatible with
complex peptide scaffolds. Furthermore, leveraging the exceptional chemoselectivity, we have showcased its capability as an
efficient bioconjugation tool on a model protein under
biomolecule-compatible conditions. A combined experimental
and computational investigation reveals that the free
sulfilimines could facilitate the oxidation of Cu(I) to Cu(II)
via an inner-sphere electron-transfer process, which allows the
C−N bond formation in the absence of external oxidants. The
protocol described herein represents an appealing alternative
to classic oxidative C−N coupling strategies, enabling greater
substrate generality and eliminating byproducts from oxidants.
Our simple copper catalytic system provides a promising
solution for addressing the challenge associated with the
construction of a sulfilimine covalent cross-link in the context
of proteins, which is currently under investigation in our
laboratory.
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Figure 4. Control experiments of the copper-catalyzed arylation of
sulfilimines.
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Three possible mechanisms for the formation of hydrogen
gas were considered. The first formed hydrogen through a fivemembered transition state, the second formed hydrogen
through a H• arising from isopropanol (iPrOH), and the
third formed hydrogen through a four-membered transition
state arising from the initial formation of a copper hydride. The
five-membered pathway formed hydrogen gas directly through
a union between the hydrogen atoms of iPrOH and 1a when
coordinated to copper (Figure S14). This pathway proceeds
from a Cu(I) to a Cu(III) species. The transition state barrier
for this pathway is 91.1 kcal/mol, which is far too high to be
feasible. From Cu(II), the corresponding five-membered
transition state could not be located, and versions with a
frozen core indicated that any such transition state would be
very high in energy.
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EXPERIMENTAL SECTION
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Typical Procedure for the Terminal Oxidant-Free Chan−
Lam Coupling Reaction. To an oven-dried microwave vial
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Figure 5. Mechanistic studies. (a) EPR spectra, (b) UV−vis spectra, (c) energy profile for the formation of hydrogen gas through a radical
mechanism, and (d) energy profile for the formation of hydrogen gas through a copper hydride species. Free energy for both pathways was
computed using SMD-2-propanol-BP86-d3/6-311G(d,p), Cu:SDD//BP86-d3/6-311G(d,p), and Cu:SDD. (e) Proposed mechanism of the
terminal oxidant-free Chan−Lam coupling.
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equipped with a stir bar free sulfilimine 1 (0.3 mmol, 1.0 equiv),
boronic acid 2 (0.45 mmol, 1.5 equiv), and CuBr (2.2 mg, 0.015
mmol, 5 mol %) were added under an argon atmosphere in a dry box.
The vial was capped with a septum and removed from the dry box.
iPrOH (3.0 mL) was added to the reaction vial via syringe, and the
reaction solution was stirred at room temperature under an argon
atmosphere for 24 h. Upon completion of the reaction, the vial was
opened to air, and the reaction mixture was passed through a short
pad of silica gel. The pad was then rinsed with 20:1
dichloromethane:methanol (20.0 mL). The solvent was removed
under reduced pressure. The residue was purified by flash
chromatography to afford the purified product.
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.2c04627.
Detailed experimental procedures, characterization data,
NMR spectra of new compounds, detailed computational study, and calculated structures are included
(PDF)
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Tingting Meng − School of Chemistry and Chemical
Engineering, Harbin Institute of Technology, Harbin 150001,
P. R. China; Shenzhen Grubbs Institute, Department of
Chemistry and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen, Guangdong 518055, P. R. China
Lucille A. Wells − Department of Chemistry, Roy and Diana
Vagelos Laboratories, Penn/Merck Laboratory for HighThroughput Experimentation, University of Pennsylvania,
Philadelphia, Pennsylvania 19104, United States
Tianxin Wang − Shenzhen Grubbs Institute, Department of
Chemistry and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen, Guangdong 518055, P. R. China
Jinyu Wang − Shenzhen Grubbs Institute, Department of
Chemistry and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen, Guangdong 518055, P. R. China
Shishuo Zhang − Shenzhen Grubbs Institute, Department of
Chemistry and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen, Guangdong 518055, P. R. China
Jie Wang − Shenzhen Grubbs Institute, Department of
Chemistry and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen, Guangdong 518055, P. R. China; orcid.org/
0000-0001-7602-5050
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.2c04627
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Author Contributions
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⊥
T.M. and L.A.W. contributed equally to this work.
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Notes
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The authors declare no competing financial interest.
REFERENCES
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Authors
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Marisa C. Kozlowski − Department of Chemistry, Roy and
Diana Vagelos Laboratories, Penn/Merck Laboratory for
High-Throughput Experimentation, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, United
States; orcid.org/0000-0002-4225-7125;
Email: marisa@sas.upenn.edu
Tiezheng Jia − Shenzhen Grubbs Institute, Department of
Chemistry and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen, Guangdong 518055, P. R. China; State Key
Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, P. R. China; orcid.org/00000002-9106-2842; Email: jiatz@sustech.edu.cn
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AUTHOR INFORMATION
Corresponding Authors
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Article
ACKNOWLEDGMENTS
T.J. thanks the Guangdong-Joint Foundation of Shenzhen
(2021B1515120046), the Natural Science Foundation of
Guangdong Province (2022A1515011770), the Shenzhen
Nobel Prize Scientists Laboratory Project (C17783101), and
the Guangdong Provincial Key Laboratory of Catalysis
(2020B121201002) for financial support. M.C.K. thanks the
NIH (R35 GM131902) for financial support and XSEDE (TGCHE120052) for computational support. The authors are also
very grateful to Prof. Lele Duan and Haiyuan Zou (SUSTech)
for the assistance in GC and Dr. Yang Yu (SUSTech) in
HRMS. They also acknowledge the assistance of SUSTech
Core Research Facilities.
sı Supporting Information
*
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